Heroin abuse increases the risk of HIV infection and may exacerbate HIV encephalitis (HIVE). Since a large percentage of newly infected HIV patients abuse opiates, this enhancement of disease process has serious medical and social consequences. Little is known about cellular mechanisms by which opiates accelerate and enhance the CNS neuropathology associated with HIV infection, and synergism may be multifactorial. Recent evidence from our labs and others suggests that precursors of CNS cells can be targets of HIV-mediated toxicity. Our central hypothesis is that HIV proteins and/or HIV can target glial precursors in the CNS, and that opiates act synergistically to enhance the toxic effects of HIV. Even modest toxicity toward this population would, over time, alter the balance of glial cells and glial-neuronal relationships in the mature CNS. The net consequences would depend upon the differential sensitivity of glial precursors at each stage of maturation, and likely would be influences by the onset and duration of disease, and timing of therapeutic regimens. Based on initial data showing that glial precursors and their progeny have different responses to Tat and morphine exposure, we propose aims that test if HIV viral proteins or HIV in combination with opiates alter production and/or survival of progenitors in vivo, thereby altering CNS mature glial populations (Aims 1 & 2). We also use in vitro approaches in isolated cells and more complex systems to assess intracellular pathways activated by viral toxins and opiates in glial progenitors (Aim 3). Aims 1 and 2 utilize three in vivo mouse models. The first is an inducible transgenic mouse expressing HIV-1 Tat in astroglia. The second is a gp120 i.c.v. injection model. The third is a SCID mouse injected with HIV-infected human monocytes. These aims assess glial progenitors in mature and neonatal mice, to understand the effects of HIV exposure on progenitors and glial populations in adult vs. pediatric situations. Human HIV tissue is also studied. Aim 3 uses pharmacologic and molecular strategies to explore disruptions in intracellular signaling in murine and human cells in vitro. Studies assess lethal and sub-lethal effects, and include pharmacological and genetic approaches to show that opiate-HIV synergism is mediated through mu-opioid receptors. In summary, there are compelling reasons to explore HIV-opiate synergy. Our comprehensive approach will provide accurate data about the susceptibility of glial precursors to HIV and opiate exposure in vivo, and potential long-term consequences to CNS pathology. HIV infection and injection drug use are interlinked epidemics with devastating consequences for public health. This project examines interactive effects between HIV and opiate drugs of abuse on glial progenitors and mature glial populations in the brain to define synergistic mechanisms that promote CNS neuropathology